Primary Biliary Cirrhosis (PBC) is an autoimmune liver disease that affects mainly women, diminishes quality of life, and often leads to liver transplantation despite therapy with ursodeoxycholic acid (UDCA). Some 30% of patients do not respond robustly to UDCA therapy (i.e., non-responders) and tend towards progressive disease and worse prognosis. Notwithstanding recent progress in the field of PBC genetics, our current knowledge regarding PBC pathogenesis has not led to informed development of novel therapies to benefit PBC patients. In 2002, we created the Mayo Clinic PBC Genetic Epidemiology (MCPGE) Resource to better understand the genetic and non-genetic risks of the disease, and aimed at improving the prognosis and therapy of PBC. This ongoing resource comprises of extensive clinical data on disease progression and outcomes, prospectively collected questionnaire data regarding life-styles, environmental exposures, and family history, as well as biospecimens including DNA, serum, plasma, and lymphoblastoid cell-lines (LCLs). To date, 919 PBC patients and 1,043 first-degree relatives are consenting participants in the MCPGE, making it the largest resource of its kind in North America. We have also established productive collaborations with investigators of the Canadian PBC cohort and the UK PBC Consortium to share resources and validate results in the interest of our common goals. Over the past 5 years we have played a key role in discovering and validating a majority of the 26 genetic loci currently known to be associated with PBC, and established paradigms of gene X gene and gene X environment interactions, which modify PBC risk. Yet, important questions from the standpoint of PBC genetic architecture related to clinical outcomes and disease pathobiology that could revolutionize the understanding and therapy of PBC remain untapped. In this application, we propose to test several hypotheses addressing our Specific Aims: In Aim 1 we will discover and validate genetic variants that impact PBC outcomes, including those affecting response to UDCA therapy and transplant-free survival. In Aim 2 we will better define the genomic architecture of PBC through identification and validation of novel rare (Aim 2a: familial studies) and low-effect common (Aim 2b: case-control studies) genetic variants, as well as genetic interactions (Aim 2c: gene X gene, gene X environment studies) that could explain the missing heritability from prior PBC GWAS and fine mapping studies. In, Aim 3 we will start examining biological mechanisms underlying observed PBC genetic associations using RNA sequencing of patient and control LCLs and expression and splicing quantitative trait locus (eQTL, spQTL) mapping. Overall, this study will further our understanding of genetic variants and disease mechanisms of PBC that have meaningful clinical impact on individualizing therapy and prognosis.